期刊
AMERICAN JOURNAL OF PATHOLOGY
卷 190, 期 3, 页码 642-659出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.ajpath.2019.11.014
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资金
- NIH [K08DK089002]
- Brigham and Women's Hospital Faculty Career Development Award
- University of Alabama at Birmingham/University of California-San Diego O'Brien Core Center for Acute Kidney Injury Research grant [NIH P30 DK 079337]
Ischemia due to hypoperfusion is one of the most common forms of acute kidney injury. We hypothesized that kidney hypoxia initiates the up-regulation of miR-218 expression in endothelial progenitor cells (EPCs) to guide endocapillary repair. M urine renal artery-derived EPCs (CD34(+)/CD105(-)) showed down-regulation of mmu-Mir218-5p/U5 RNA ratio after ischemic injury, while in human renal arteries, MIR218-5p expression was up-regulated after ischemic injury. MIR218 expression was clarified in cell culture experiments in which increases in both SLIT3 and M1R218-2-5p expressions were observed after 5 minutes of hypoxia. ROB01 transcript, a downstream target of MIR218-2-5p, showed inverse expression to MIR218-2-5p. EPCs transfected with a MIR218-5p inhibitor in three-dimensional normoxic culture showed premature capillary formation. Organized progenitor cell movement was reconstituted when cells were co-transfected with Dicer siRNA and low-dose Mir218-5p mimic. A Mir218-2 knockout was generated to assess the significance of miR-218-2 in a mammalian model. Mir218-2-5p expression was decreased in Mir218-2(-/-) embryos at E16.5. Mir218-2(-/-) decreased CD34(+) angioblasts in the ureteric bud at E16.5 and were nonviable. Mir218-2(+/) decreased peritubular capillary density at postnatal day 14 and increased serum creatinine after ischemia in adult mice. Systemic injection of miR-218-5p decreased serum creatinine after injury. These experiments demonstrate that miR-218 expression can be triggered by hypoxia and modulates EPC migration in the kidney.
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